The invention relates to a new method of synthesis of an intermediate useful for the synthesis of epothilone B and desoxyepothilone B and derivatives thereof, as well as to certain new partial reaction sequences for the production of key intermediates.
Among cytotoxic agents for the treatment of tumors, Taxol(copyright) (Paclitaxel), a microtubule stabilizing agent, has become a very important compound with a remarkable economic success (see McGuire, W. P., et al., Ann. Int. Med. 111, 273-9 (1989)).
Taxol(copyright) has a number of disadvantages. Especially its extremely low solubility in water represents a severe problem. It has become necessary to administer Taxol in a formulation with Cremophor EL(copyright) (polyoxyethylated castor oil; BASF, Ludwigshafen, Germany) which has severe side effects, causing inter alia allergic reactions that in one case even were reported to have led to the death of a patient. More severely, certain tumor types are known to be refractory against treatment with Taxol(copyright).
Taxol(copyright) treatment is associated with a number of significant side effects and some major classes of solid tumors, namely colon and prostate, are poorly responsive to this compound (see Rowinsky E. K., loc. cit.).
The epothilones A and B are a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot. 49, 560-3 (1966); Hoefle et al., DE 41 38 042) of the formulae: 
wherein Z is hydrogen (epothilone A) or methyl (epothilone B).
These compounds have the following advantages:
(i) they show better water solubility than Taxol and are thus more appropriate for formulation; and
(ii) they have been reported to be active also against the proliferation of cells that, due to the activity of the P-glycoprotein efflux pump which renders them multidrug resistant, show resistance to the treatment with other chemotherapeutics, e.g. Taxol (see Bollag, D. M., et al., xe2x80x9cEpothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of actionxe2x80x9d, Cancer Research 55, 2325-33 (1995); and Bollag D. M., Exp. Opin. Invest. Drugs 6, 867-73 (1997); and
(iii) despite apparently sharing the same, or at least a largely overlapping binding site on the microtubule, the epothilones have been shown to be active against a Taxot(copyright)-resistant ovarian carcinoma cell line with an altered xcex2-tubulin (see Kowalski, R. J., et al., J. Biol. Chem. 272(4), 2534-2541 (1997)).
Due to their impressive biological profile, multiple initial efforts towards the synthesis of epothilones appeared almost simultaneously in the literature. Three groups described total syntheses of epothilone A, and two total syntheses of epothilone B appeared concurrently as well. In addition, a flood of papers appeared which presented partial solutions towards the synthesis of epothilones. Since these studies, many derivatives have been synthesized and their biological profiles have been tested.
Especially epothilone B provides important biological properties that are exemplary for other epothilones:
Epothilone B is appropriate preferably in the treatment of proliferative diseases, such as of gastrointestinal tumors, more preferably (1) a tumor of the colon AND/OR the rectum (colorectal tumor), especially if it is refractory to a (meaning at least one) representative of the taxane class of anti-cancer agents, in particular paclitaxel, AND/OR at least one standard treatment with an other chemotherapeutic, especially 5-fluorouracil; (2) a tumor of the genitourinary tract, more preferably a tumor of the prostate, including primary and metastatic tumors, especially if refractory to hormone treatment (xe2x80x9chormone refractory prostate cancerxe2x80x9d) and/or treatment with other standard chemotherapeutics; (3) an epidermoid tumor, more preferably an epidermoid head and neck tumor, most preferably a mouth tumor; (4) a lung tumor, more preferably a non-small cell lung tumor, especially any of these tumors that is refractory to treatment with one or more other chemotherapeutics (especially due to multidrug resistance), especially to treatment with a member of the taxane class of anti-cancer agents, in particular TAXOL(copyright); or (5) a breast tumor, more preferably one that is multidrug resistant, especially refractory to treatment with a member of the taxane class of anti-cancer agents, in particular TAXOL(copyright); relating especially also to the treatment of a multidrug resistant lung tumor (preferably a non-small cell lung tumor), a multidrug resistant breast tumor, or a multidrug resistant epidermoid tumor, or in a broader sense of the invention to a treatment schedule for the treatment of an aforementioned or (in a broader sense of the invention) any other tumor.
Epothilone B is preferably used weekly or three-weekly; preferably for weekly treatment the dose is between about 0.1 and about 6, preferably about 0.1 and about 5 mg/m2, more preferably about 0.1 and about 3 mg/m2, even more preferably 0.1 and 1.7 mg/m2, most preferably about 0.3 and about 1 mg/m2; for three-weekly treatment (treatment every three weeks or every third week) the dose is between about 0.3 and about 18 mg/m2, preferably about 0.3 and about 15 mg/m2, more preferably about 0.3 and about 12 mg/m2, even more preferably about 0.3 and about 7.5 mg/m2, still more preferably about 0.3 and about 5 mg/M2, most preferably about 1.0 and about 3.0 mg/m2. This dose is preferably administered to the human by intravenous (i.v.) administration during 2 to 180 min, preferably 2 to 120 min, more preferably during about 5 to about 30 min, most preferably during about 10 to about 30 min, e.g. during about 30 min.
Preferably, especially in the case of weekly treatment, rest periods of more than one week, more preferably of two to ten weeks, more preferably three to six weeks after the preceding treatment may be necessary after for example 3, 4, 6, 8, or more treatment cycles, depending on patient condition, to allow for sufficient recovery from the preceding treatment.
The pharmaceutical compositions comprise from about 0.00002 to about 95%, especially (e.g. in the case of infusion dilutions that are ready for use) of 0.0001 to 0.02%, or (for example in case of infusion concentrates) from about 0.1% to about 95%, preferably from about 20% to about 90%, active ingredient (weight by weight, in each case). Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
Preferred is an infusion formulation comprising epothilone B and a pharmaceutically acceptable organic solvent. The pharmaceutically acceptable organic solvent used in a formulation according to the invention may be chosen from any such organic solvent known in the art. Preferably the solvent is selected from alcohol, e.g. absolute ethanol or ethanol/water mixtures, more preferably 70% ethanol, polyethylene glycol 300, polyethylene glycol 400, polypropylene glycol or N-methylpyrrolidone, most preferably polypropylene glycol or 70% ethanol or especially polyethylene glycol 300.
Epothilone B may preferably be present in the formulation in a concentration of about 0.1 to about 100 mg/ml, more preferably about 1 to about 100 mg/ml, still more preferably about 1 to about 10 mg/ml (especially in infusion concentrates).
It is a goal of the present invention to provide novel routes to manufacture an intermediate for the synthesis of epothilone B and its predecessor, desoxyepothilone B.
In contrast to a published synthesis by Nicolaou et al. (see J. Am. Chem. Soc. 119, 7974-91 (1997)) for the synthesis of epothilone B, the new route is more convergent, that is, it is based on three rather than two key fragments that have to be assembled to the final product. The disadvantage of the prior art two-fragment strategy consists in the fact that many more steps are required to prepare the individual fragment. Therefore the new synthesis offers large advantages.
The invention relates to a formal total synthesis route via an intermediate appropriate for the synthesis of epothilone B and analogues thereof. The approach uses macrolactonization for the final ring closure and provides an especially convergent strategy to obtain the key building blocks.
The invention also especially relates to the synthesis of the aldehyde 17 and the aldehyde 18 (see reaction scheme 2) starting from (+)-malic acid, which is largely unrelated to published synthesis of these compounds and is much more practical.
The invention also especially relates to new processes of manufacture for ethyl ketone 30, either via the ester 26 (scheme 4) or acyl sultam 31. The latter compound has been described in the literature (see Synlett (1997), 623). However, if the procedure recommended in that publication is followed, the wrong (namely the 3R-) enantiomer is obtained instead of the desired isomer 31, which is required for the synthesis of epothilones.
The invention also especially relates to the synthesis of 19 via a Pd-catalyzed coupling reaction, which offers the large advantage of highly selective formation of a cis-bond at the double bond connecting carbon atoms 12 and 13 in epothilone B as well as to the new intermediate 19. This compound has not been described previously as a homogenous double bond isomer at the C12-C13 double bond of epothilone B. Surprisingly, the above reaction is stereoselective only for the methyl substituent Z found in the formula of epothilone B given in the introduction.
The invention relates especially to a new method for the synthesis of an intermediate of the formula I 
wherein R is a heterocyclyl moiety and X1, X2, X3 and X4 are, independently of each other, protecting groups.
The intermediate of the formula I can then be used for the synthesis of epothilone B and analogues thereof via various steps including macrolactonization and epoxidation, using methods known in the art, see especially Nicolaou et al., J. Am. Chem. Soc. 119, 7974-91 (1997). If the epoxidation step is omitted (and, if present, protecting groups are cleaved of), desoxyepothilone B, the analogue of epothilone B where instead of the oxirane ring a double bond is present, can be synthesized.
Within the present disclosure, the general definitions used hereinbefore and hereinafter preferably have the following meaning, if not indicated otherwise:
A heterocyclyl moiety R is preferably a monocyclic moiety with 5 or 6 ring atoms, wherein 1 to 3, especially one or two, ring carbon atoms each are replaced by a heteroatom selected from nitrogen, oxygen or sulfur; the heterocyclic moiety may be unsubstituted or substituted by one or more substituents that are preferably independently selected from the group consisting of oxo, lower alkyl, especially methyl, hydroxy-lower alkyl, especially hydroxymethyl, lower alkylmercapto, especially methylmercapto, phenylmercapto, amino, mono- or di-lower. alkylamino, especially dimethylamino, halogen-lower alkyl, such as fluoromethyl, or acyloxy-lower alkyl, such as lower alkanoyloxy-lower alkyl, e.g. 5-acetyloxy-pentyl or acetyloxymethyl.
Most preferably, the heterocyclyl moiety has any one of the following formulae: 
wherein Rx is acyl, especially lower alkanoyl, such as acetyl;
Most preferably, the moiety R has the formula I 
A protecting group is especially selected from the group comprising a silyl protecting group, especially diaryl-lower alkyl-silyl, such as diphenyl-tert-butylsilyl, or more preferably tri-lower alkylsilyl, such as tert-butyldimethylsilyl or trimethylsilyl; lower alkanoyl, such as acetyl; benzoyl; lower alkoxycarbonyl, such as tertutoxycarbonyl; tetrahydropyranyl; phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl; and unsubstituted or substituted 1-phenyl-lower alkyl, such as benzyl or p-methoxybenzyl.
The protecting groups may be present in any precursors and intermediates and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. In certain cases, the protecting groups may, in addition to this protection, effect a selective, typically stereoselective, course of reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum Press, London and New York 1973, in T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, New York 1981, in xe2x80x9cThe Peptidesxe2x80x9d; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in xe2x80x9cMethoden der organischen Chemiexe2x80x9d (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/l, Georg Thieme Vedag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, xe2x80x9cAminosxc3xa4uren, Peptide, Proteinexe2x80x9d (Amino adds, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, xe2x80x9cChemie der Kohlenhydrate: Monosaccharide und Derivatexe2x80x9d (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.
The prefix xe2x80x9clowerxe2x80x9d means that the respective moiety preferably has up to and including a maximum of 7 carbon atoms, more preferably up to 4 carbon atoms.
Lower alkyl can be linear or branched and is especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
Halogen is preferably fluorine, chlorine, bromine or iodine.
Any reference to other documents or publications within this application means that the respective document or publication is included by reference into the present disclosure.
The process steps making up the process of the invention and the preferred aspects thereof can be described preferably as follows:
Hereinbefore and hereinafter, the definitions of the moieties R, X1, X2, X3 and X4 have the meaning given under formula I, if not indicated otherwise. A moiety X, where mentioned, stands for a protecting group as defined above (and may, depending on the exact position, correspond to any of X1, X2, X3 and X4 if appropriate).
The reaction sequence starts with a compound of the formula II 
wherein Y is the radical of an organic or inorganic acid devoid of its dissociable hydrogen, e.g. halogen, especially chlorine, and X is a protecting group as described above, especially benzyl; which is reacted with an oxazolidone of the formula III 
wherein Zxe2x80x2 is lower alkyl, e.g. isopropyl, or preferably phenyl-lower alkyl, especially benzyl, in an appropriate solvent, e.g. tetrahydrofuran, in the presence of a strong base, especially methyl magnesium bromide, and then of an appropriate tertiary amino base, such as 4-di-methylaminopyridine; or preferably of an alkalimetal alkylid, such as n-butyl-lithium; at low temperatures, e.g. in the range from xe2x88x9280 to +10xc2x0 C., yielding a compound of the formula IV, 
wherein X and Zxe2x80x2 have the meanings given above; (IV) is then C-methlyated, e.g. with a halomethane, especially methyliodide, in the presence of a strong base, e.g. sodium hexamethyldisilazide, to yield a compound of the formula V, 
wherein X and Zxe2x80x2 are defined as above; from that compound, then a compound of the formula VI, 
wherein X is as given above is set free by reductive cleavage, e.g. by reaction with a complex hydride, such as lithium aluminium hydride; then, a protecting group Xxe2x80x2 selected from the protecting groups mentioned above for X1 to X4, but different from X in formula VI, preferably tert-butyl-dimethylsilyl, is introduced at the free hydroxy group that allows that the protecting group X in the compound of formula VI can be cleaved off without affecting the newly introduced protecting group, e.g. by reaction with an alkylsilylhalogenide, such as tert-butyldimethylsilyl chloride, to yield a bis-protected compound of the formula VII, 
with X and Xxe2x80x2 as described above; from this compound, then the protecting group X, preferably benzyl, is cleaved off under appropriate conditions, e.g. by catalytic transfer hydrogenolysis, reaction with lithium 4,4xe2x80x2-di-tert-butyl-biphenyl or by catalytic hydrogenation, to yield a compound of the formula VIII, 
with Xxe2x80x2 as defined for the compound of the formula VII; that compound VIII is then reacted with a halogenide of an organic sulfonic acid to yield the corresponding sulfonic acid ester of the formula IX, 
wherein Q is organic sulfonyl, especially alkanesulfonyl, such as methanesulfonyl, and that sulfonyl ester is then reacted with a metal iodide, especially sodium iodide, to yield the corresponding iodide compound of the formula X, 
with Xxe2x80x2 as defined above.
This is the synthesis of one of the three intermediates for the convergent synthesis.
Independently from that sequence of reactions,
a) a compound of the formula XI, 
wherein R is as described under formula I and Hal is halogen, especially chlorine, is reacted with a tri-alkyl phosphite, especially triethyl phosphite, to yield a phosphonate compound of the formula XII, 
wherein R is as defined under formula I and each of A is alkyl, especially ethyl.
Independently, (5S)-(2,2-cyclohexylidene-)-4-oxo-1,3-dioxolane (synthesized starting from L-(xe2x88x92)-malic acid, see Hanessian et al., J. Orgn. Chem. 58, 7768-81 (1993)) is reacted with BH3-Me2S complex=dimethylsulfide BH3xc3x97Me2S ist verzichtbarto yield 3(S)-dihydro-3-hydroxy-2(3H)-furanone (compound 11 in reaction scheme 2 below); that is then protected by introduction of a protecting group X4, especially using a lower alkylsilyl halogenide, such as tert-butyldimethylsilylchloride, to yield a compound of the formula XIII, 
wherein X4 is a protecting group, especially tert-butyldimethylsilyl; the compound of formula XIII is then reacted with an methyl metal or methyl metal derivative, especially methyl lithium, to the novel compound of the formula XIV, 
wherein X4 is as defined under formula XIII; the compound of formula XIV is reacted with a further reagent capable of introducing a protecting group, especially an alkylsilyl halogenide, such as tert-butyldimethylsilyl chloride, yielding a compound of the formula XV, 
wherein X and X4 are a protecting group, especially tert-butyldimethylsilyl, which compound is then reacted with a phosphonate compound of the formula XII given above in the presence of a strong base, especially n-butyl lithium, yielding a compound of the formula XVII, 
wherein X and X4 are as defined under formula XIII and R is as defined under formula I; the compound of the formula XVII is then deprotected partially under appropriate conditions (e.g., if X is tert-butyldimethylsilyl, by using aqueous hydrofluoric acid) to give a compound of the formula XVIII, 
wherein the moieties X4 and R are as defined under formula XVII; the compound of the formula XVIII is oxidized selectively, e.g. using dimethylsulfoxide and oxalylchloride in dichloromethane, to the corresponding aldehyde of the formula XIX, 
wherein R and X4 are as defined under formula XVII, which is then, by reaction with a strong base, especially n-butyl lithium, and iodine in the presence of triphenylphosphonium iodide (either with isolation of the iodoethyl phosphonium iodide or in a one pot synthesis), and subsequent addition of a different or the same base as above, especially sodium hexamethyidisilazide, converted into a compound of the formula XX, 
(this reaction being highly specific in yielding mainly or purely the cis-compound wherein R and X4 are as defined under formula XVII.
This reaction sequence is allowing for the introduction of a large variety of heterocyclic moieties R and thus providing an important new way of synthesizing analogs of epothilone B and desoxyepothilone B wherein R has one of the other meanings than 2-methyfthiazolyl given above under formula (I)
The sequence of reactions from XIII to XV, especially the reaction from XIII to XIV and the reaction from XIV to XV, as well as the whole sequence leading from L-malic acid to XX (as described in the examples), are new and form a special part of the invention.
The compounds of the formulae XIV (especially compound 13 in scheme 2), XVII (if R is other than 2-methylthiazol-4-yl and X4 is other than tert-butyldimethylsilyl) (especially 15 in scheme 2), XVIII (if R is other than 2-methylthiazol-4-yl and X4 is other than tert-buityldimethylsilyl) (especially 16 in scheme 2), the compound of formula XX if R is other than 2-methylthiazol-4-yl, and compound 18 in scheme 2, are new and are also part of the invention.
The compound of the formula XX is the second of the three intermediates for the convergent synthesis.
The third intermediate for the convergent synthesis is manufactured preferably by one of the two ways (a) and (b) described hereinafter:
(a) (see also scheme 4) Diethylketon is reacted in the presence of zinc dust (activated, e.g. with 1,2-dibromoethane) in the presence of B(OCH3)3 with ethyl 2-bromo-2-methylpropanoate (Fluka, Buchs, Schweiz) to ethyl 2,2-dimethyl-3-ethyl-3-hydroxypentanoate 22, which is then reacted with a dehydrating agent, especially phosphorus pentoxide, to ethyl (E)-2,2-dimethyl-2-ethyl-3-pentenoate 23; which is then reacted in the presence of an appropriate complex hydfide, e.g. lithium aluminium hydride, to E-2,2-dimethyl-3-ethyl-3-penten-1-ol 24; this is then oxidised with an appropriate oxidant, e.g. dimethylsulfoxide in dichloromethane and oxalyl chloride, to (E)-2,2-dimethyl-3-ethyl-3-pentenal 25, which is then reacted with (S)-(xe2x88x92)-2-hydroxy-1,2,2-triphenyl acetate (FLUKA) in the presence of a strong base, e.g. Li-di-isopropylamide, to (1S)-2,2,1-triphenyl-2-hydroxyethyl-(3S,E)-4,4-dimethyl-5-ethyl-3-hydro-xy-5-heptenoate 26; that compound is transformed, by reaction with an appropriate complex hydride, e.g. lithium aluminium hydride, into (S)-(E)-4,4-dimethyl-5-ethyl-5-heptene-1,3-diol 28, which is then converted, by reaction with acetone in the presence of anhydrous copper sulfate, a strong organic acid, e.g. p-toluene sulfonic acid, and a tertiarry nitrogen base, e.g. pyridine, to give (S)-(E)-2,2-dimethyl-[1,3]dioxan-4-yl)-3-ethyl-2-methyl-pent-3-ene 29; this compound is then converted to the third intermediate for the convergent synthesis, the ethyl ketone (S)-2-(2,2-dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-one 30 by ozonolysis.
(b) (see scheme 3) Alternatively, 30 can be obtained advantageously by reaction of (2R)-N-acetylbo mane-10,2-sultam (see Tetrahedron Lett. 33, 2439 (1992)) in the presence of a dialkylborane triflate or dialkylborane chloride, especially diethylborane triflate (which can, but does not have to be, generated in situ from triethylborane and CF3SO3H) and after addition of a tertiary nitrogen base, e.g. diisopropylethyl amine, with 2,2-dimethyl-3oxo-pentanal (see J. Am. Chem. Soc. 119, 7974 (1997)) that leads to the sultam product 31, which is then reacted, in the presence of a tertiary nitrogen base, such as 2,6-lutidine, with a reagent appropriate for the introduction of a protecting group, e.g. an alkylsilylhalogenide, especially tert-butyldimethylsilyl-triflate, to give a compound of the formula XXI 
wherein X is a protecting group, especially tert-butyldimethylsilyl (especially compound 32); the compound of formula XXI is then converted into the corresponding free acid of the formula XXII by reaction with an appropriate aqueous base, e.g. LiOH, NaOH, KOH, or LiOOH, especially with LiOOH 
wherein X is as defined under formula XXI (especially compound 33); the compound of formula XXII is then reduced to the corresponding alcohol of the formula XXIII 
wherein X is as defined under formula XXI (especially compound 34), by reaction eg. with Borane/dimethylsulfide, and finally that compound is deprotected and transformed into compound 30 by reaction in acetone/acid, such as acetoneltrifluoroacetic acid.
Thus, the third intermediate for the convergent synthesis of the compound of the formula I is prepared.
In a next step, first the two intermediates of the formulae X and XX (preferably compounds 8 and 18 in scheme 5) are coupled by reaction of the compound of the formula X with a suspension of powdered Zn/Cu couple in the presence of an activator, e.g. 1,2-dibromoethane, in the presence of halotrialkylsilane, such as chlorotrimethylsilane (i necessary with addition of trifluoromethanesulfonate and catalytic amounts of mercury(II) acetate to complete the first part of the reaction, and then addition of XX and a Pd(O)-complex yielding a compound of the formula XXIV, 
wherein X and X4 each are a protecting group, especially tert-butyldimethylsilyl, and R is as defined under formula I; the advantage of this coupling is that it yields the cis-isomer of the compound of the formula XXIV in high yield and stereospecificity the compound of the formula XIV is then selectively deprotected, e.g. (in the case of X=alkylsilyl, especially tertbutyl-dimethylsilyl) by campher sulfonic acid, to give a compound of the formula XXV, 
wherein X4 and R are as defined under formula XXIV; the compound of the formula XXV is then oxidized with an appropriate oxidant, e.g. Dess-Martin periodinane, to the corresponding aldehyde of the formula XXVI 
wherein X4 and R are as defined under formula XXIV.
The compounds of the formulae XXIV and XXV in essentially isomeric pure cis-form, especially if R is other than 2-methylthiazolyl) are new and also part of the invention, as well as the coupling reaction of the compounds of the formulae X and XX to the compound of the formula XXIV.
The third intermediate of the convergent synthesis, compound 30, is then reacted with the compound of the formula XXVI (preferably compound 21) in an Aldol reaction, preferably by reaction in the presence of lithium diisopropylamide (LDA) that is first reacted with compound 30, followed by addition of the compound of the formula XXVI, resulting in a compound of the formula XXVII, 
wherein X4 and R are as defined under formula I; the compound of the formula XXVII is then deprotected under removal of the acetal moiety, e.g. using pyridinium-p-toluenesulfonate, yielding a compound of the formula XXVIII, 
wherein X4 and R are as defined under formula I; finally, the compound of the formula I is obtained by introduction of protecting groups X1, X2 and X3 with appropriate reagents, e.g. alkylsilyl halogenides or alkylsilyl trifluoromethanesulfonates, especially tert-butyl-dimethylsilyltrifluoromethanesulfonate, in the presence of an appropriate tertiary nitrogen base, such as 2,6-lutidine.
The compound of the formula XXIV, especially where R is other than 2-methylthiazol-4-yl, is also part of the invention.
All reactions are done in appropriate solvents, at appropriate temperatures and, if necessary, under an inert gas, such as argon or nitrogen.
The invention relates also to any novel intermediates and to any novel ways of synthesis of such intermediates, as well as to novel single reaction steps, especially those leading to such novel intermediates, and combinations of such reaction steps.
The skilled person will understand that the reaction conditions given above can be replaced by analogous reaction conditions that are in principle known in the art. In addition, the skilled person will be able to select the appropriate specific reaction conditions for the reaction steps given hereinbelow and hereinafter where reactions are described generally herein. All those reaction conditions are included in the scope of the present invention.
The reactions given above are preferably carried out under conditions analogous to those given in the Examples.
The invention relates most especially to the above reaction sequences where the respective intermediates and educts mentioned in the examples are used instead of the general formulae II to presented above.
The starting materials are known, can be synthesized according to known procedures, are available commercially or can be synthesized in analogy to the materials given below in the examples.